Aus dem BIH Centrum für Regenerative Therapien (BCRT), Julius Wolff Institut (JWI) und dem Centrum für Muskuloskeletale Chirurgie (CMSC) – der
Medizinischen Fakultät, Charité – Universitätsmedizin Berlin
DISSERTATION
Complication rate analysis of proximal humerus fracture surgery in elderly patients –
Guiding the benefit-risk assessment for an immunomodulatory therapy
zur Erlangung des akademischen Grades Doctor medicinae (Dr. med.)
vorgelegt der Medizinischen Fakultät Charité – Universitätsmedizin Berlin
von
Hisham Elazaly
aus Ägypten
Datum der Promotion: 04.06.2021
2
Table of Contents
List of Tables ... 4
List of Figures ... 5
List of Abbreviations ... 6
Zusammenfassung ... 8
Abstract ... 10
Chapter 1 : Introduction ... 12
1.1 Proximal Humerus Fractures (PHF) ... 12
1.2 Classification of PHF ... 13
1.3 Current clinical management strategies ... 14
1.3.1 Surgery as the first-line of treatment ... 15
1.3.2 PHF evaluation and patient considerations ... 17
1.3.3 Individualization of the treatment ... 18
1.4 Treatment outcomes and complication rates ... 19
1.5 Complication patterns and associated risk factors ... 20
1.5.1 Complication patterns ... 20
1.5.2 Associated risk factors ... 22
1.6 Novel concepts in bone regeneration ... 24
1.6.1 The potential benefits of Iloprost in bone healing ... 25
1.7 Clinical trial approval ... 27
1.7.1 Ethics committee ... 27
1.7.2 Federal Institute for Drugs and Medical Devices (BfArM) ... 29
1.8 Aims of the study ... 30
Chapter 2 : Methods ... 32
2.1 Retrospective study ... 32
2.1.1 Literature review and formulating the research question ... 32
2.1.2 Study center ... 33
2.1.3 Study design ... 33
2.1.4 Patient selection ... 33
2.1.4.1 Inclusion criteria ... 34
2.1.4.2 Exclusion criteria ... 34
2.1.5 Data search and collection ... 34
3
2.1.6 Patients data verification ... 35
2.1.7 Statistical analysis ... 35
2.2 The development of a scientifically sound clinical testing strategy ... 35
Chapter 3 : Results ... 37
3.1 Literature review ... 37
3.2 Retrospective study ... 48
3.2.1 Treatment approach and fracture classification ... 49
3.2.2 Overall complication rates ... 50
3.2.3 Complication frequencies in each fracture type ... 50
3.2.4 Complication frequencies in each fracture type and surgical approach... 51
3.2.5 Complication patterns and revision surgeries ... 53
3.3 Devising a clinical testing strategy ... 57
3.3.1 The proposed study design ... 58
3.3.2 Determining the dosage of the investigational drug ... 59
3.3.3 Selecting clinically representative endpoints and relevant controls ... 61
3.3.4 Identifying inclusion and exclusion criteria to assess the suitability of the study population ... 63
3.3.5 Identifying potential harms (Adverse event (AE) and serious AE (SAE)) ... 64
3.3.6 Establishing clinical monitoring measures during the infusion of Iloprost ... 66
3.3.7 Establishing an overall benefit-risk assessment of the investigational drug ... 68
Chapter 4 : Discussion ... 72
Retrospective analysis of patients suffering from PHF ... 73
Developing and initiating a trial to analyze Iloprost treatment in PHF patients ... 76
Chapter 5 : Summary ... 83
References ... 87
Statutory Declaration ... 108
Lebenslauf ... 109
Acknowledgements ... 111
4 List of Tables
Table 1: Reported complication rates for locking plate fixation in proximal humerus fracture ... 20
Table 2: Overview of the studies included in the literature review... 39
Table 3: Overview of reported complications in the PHILOS studies ... 44
Table 4: Overview of reported complications in the intramedullary nail studies ... 45
Table 5: Overview of reported complications in the Hemiarthroplasty studies ... 46
Table 6: Overview of reported complications in the reverse shoulder arthroplasty (RSA) studies ... 47
Table 7: Demographic and clinical characteristics of the study patients ... 49
Table 8: Treatment approach (arthroplasty vs. PHILOS) and fracture classification ... 49
Table 9: Overall complication rates according to surgical technique ... 50
Table 10: Complication frequencies in each fracture type ... 51
Table 11: Logistic regression model for complications concerning either treatment or fracture classification. ... 51
Table 12: Complication frequencies in each fracture type and surgical approach ... 52
Table 13: Logistic regression model for the effect of fracture classification on the complication rate for PHILOS fixation. ... 52
Table 14: Logistic regression model for the effect of surgical technique on complication rate in 4-part fracture ... 53
Table 15: Complication patterns for each surgical approach ... 54
Table 16: Number of revision surgeries per treatment type and per fracture classification ... 54
Table 17: Iloprost Adverse reactions reported in clinical trials or during post-marketing surveillance in patients ... 65
5 List of Figures
Figure 1: Mechanism for low energy proximal humerus fracture in elderly individuals (9) ... 12
Figure 2: 14th coordinated population projection for Germany. (Statistisches Bundesamt; www.destatis.de) (13) ... 13
Figure 3: Neer Classification of proximal humerus fractures (15) ... 14
Figure 4: PHILOS plate (DePuy Synthes® Switzerland) (38) ... 16
Figure 5: Hemiarthroplasty 1. GLOBAL® FX™ (DePuy Synthes® Switzerland) (40) 2. Zimmer Anatomical Shoulder™ Fracture System (41) ... 16
Figure 6: reversed shoulder arthroplasty ... 17
Figure 7: Criteria of treatment choice for the 4-part PHF ... 19
Figure 8: Flow diagram of the literature review... 37
Figure 9: The retrospective medical record review study flowchart ... 48
Figure 10: Loss of reduction in PHILOS plate fixation. ... 55
Figure 11: Loss of reduction and screws cut-out in PHILOS plate fixation. ... 55
Figure 12: Infected shoulder hemiarthroplasty. ... 56
Figure 13: Number of complications in each fracture type and surgical approach ... 58
Figure 14: Flow diagram of the study design ... 59
Figure 15: Tip Apex Distance ... 62
6 List of Abbreviations
AE Adverse event
AMG Arzneimittelgesetz (Medicinal Products Act) AO Arbeitsgemeinschaft für Osteosynthesefragen AVN Avascular necrosis
BCRT Berlin Institute of Health Centre for Regenerative Therapies
BfArM Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medical Devices)
BMD Bone mineral density BMI Body mass index
CMSC Center for Musculoskeletal Surgery cPGI Carbaprostacyclin
CT Computerized Tomography CV Curriculum vitae
EMA European Medicine Agency
EudraCT European Union Drug Regulating Authorities Clinical Trials database FDA Food and drug administration
GCP Good Clinical Practice
GCP-V GCP-Verordnung (Good Clinical Practice regulation) GLUT1 Glucose transporter 1
GMO Genetically Modified Organisms GMP Good manufacturing practice HED Human Equivalent Dose HMOX heme oxygenase
IB Investigational Brochure
ICD 10 International Classification of Diseases, Tenth Revision IFN-ɣ Interferon gamma
IMP Investigational Medicinal Product IMPD Investigator Medicinal Product Dossier
IV Intravenous
K wire Kirschner wire
7 LAGeSo Landesamt für Gesundheit und Soziales (The state office for health and social
affairs)
MRI Magnetic Resonance Imaging MSCs Mesenchymal stem cells
NYHA New York Heart Association Classification ORIF Open reduction and internal fixation
PGI2 Prostaglandin I2 (Prostacyclin) PHF Proximal humerus fracture
PHILOS Proximal humeral interlocking system PPH Primary Pulmonary Hypertension
RANK Receptor activator of nuclear factor kappa-B (κB) RANKL Receptor activator of nuclear factor kappa-B (κB) ligand RSA Reverse shoulder arthroplasty
SAE Serious adverse event
SAP Systems, Applications & Products in Data Processing TAD Tip apex distance
TEMRA Terminally Differentiated Effector Memory CD8+T TNFα Tumor necrosis factor alpha
Treg Regulatory T cell subtype
VEGF Vascular endothelial growth factor μCT Micro-computed tomography
8 Zusammenfassung
Hintergrund:
Die proximale Humerusfraktur (PHF) ist die dritthäufigste traumatische Knochenfraktur in der älteren Bevölkerung. Etwa 70% der dislozierten PHF, die einer chirurgischen Behandlung bedürfen, treten bei älteren Patienten auf. Es wird erwartet, dass sich die Inzidenz der PHF in den nächsten drei Jahrzehnten verdreifachen wird. Die Behandlung von PHF bleibt problematisch, hauptsächlich aufgrund des Fehlens eines Konsens über die optimale Behandlungsstrategie. Leider ist das Ergebnis nach PHF ungünstig mit einer hohen Komplikationsrate, die zwischen verschiedenen Studien über bestimmte Behandlungsmethoden und zwischen verschiedenen Zentren variiert.
Ziel dieser Studie ist es, die Ergebnisse der chirurgischen Behandlungsstrategien, einschließlich der Komplikations- und Revisionsraten, der beiden am häufigsten durchgeführten chirurgischen Eingriffe (winkelstabile Plattenosteosynthese (PHILOS, Synthes) und Arthroplastik) bei älteren Patienten mit PHF zu analysieren. Darüber hinaus wurde der klinischen Translationsprozess eines neuen immunmodulatorischen Therapieansatzes, der die Heilungsergebnisse für die identifizierte Patientengruppe verbessern kann, in dieser Arbeit initiert.
Methodik:
Es wurde eine retrospektive Analyse aller im Centrum für Muskuloskeletale Chirurgie der Charité – Universitätsmedizin Berlin zwischen März 2017 und Juni 2018 wegen PHF chirurgisch behandelten Patienten durchgeführt, welche ein Follow-Up von mindestens sechs Monaten aufwiesen. Es wurden nur Patienten eingeschlossen, welche mit (PHILOS) oder einer Endoprothese versorgt wurden. Zusätzlich wurden die methodischen Aspekte der klinischen Umsetzung des präklinischen Wissen eines immunmodulatorischen Mittel, Iloprost, in eine solide klinische Studie beschrieben, und die erforderlichen Zulassungen von den zuständigen Behörden eingeholt.
Ergebnisse:
Es konnten 88 PHF bei 87 Probanden mit einem Durchschnittsalter von 72,9 Jahren in die Analyse eingeschlossen werden. Die Studie zeigte, dass die Gesamtkomplikationsrate bei 4-teiliger PHF, die mit PHILOS behandelt wurde, die höchsten Werte (68.8%) aufwies und damit auch höher als die Komplikationsrate bei endoprothetisch versorgten Patienten (19%) war. Die Tiefenanalyse zeigte aber auch, dass die Komplikationen nach Plattenosteosynthese einen geringeren
9 Schweregrad als die Komplikationen nach Endoprothese aufwiesen. Eine Revision erfolgte nur bei 8 von 19 Komplikationen (42%) in der PHILOS- im Vergleich zu 5 von 5 (100%) in der Endoprothetik-Gruppe. Basierend auf diesen Werten wurde ein hoher medizinischer Bedarf für neuartigen additive Therapien für die osteosynthetische Behandlung von höhergradigen PHF identifiziert.
Der Translationsprozess der immunmodulatorischen Therapie erforderte eine detaillierte Bestimmung der richtigen Dosis und des Dosierungsschemas sowie die Identifizierung von Ein- und Ausschlusskriterien, die Auswahl repräsentativer Endpunkte und die Erstellung einer Nutzen- Risiko-Bewertung. Die behördliche Zulassung wurde von LaGeSo und BfArM erfolgreich erhalten.
Schlussfolgerung:
Ältere Patienten mit 4-teiliger PHF, die mit PHILOS behandelt wurden, zeigten die höchste Komplikationsrate, und könnten durch eine additive lokale immunmodulatorische Therapie profitieren.
10 Abstract
Introduction
Proximal humerus fracture (PHF) is the third most common traumatic bone fracture in the elderly population. The incidence of PHF is expected to have tripled in the next three decades.About 70%
of displaced PHF that need surgical treatment occur in elderly patients. The treatment of PHF remains problematic, mainly due to the lack of a consensus on the optimal treatment strategy.
Moreover, the outcome after PHF surgery is currently unfavorable, with a high complication rate that varies between different studies for a given method of treatmentand between different centers.
This study aims to measure the outcome of surgical management strategies, including complication and revision rates, of the two most commonly performed surgical procedures (angle stable plate osteosynthesis (PHILOS, Synthes), and arthroplasty) in elderly patients with PHF.
Additionally, the clinical translation process of a novel immunomodulatory approach that may improve the healing outcomes for the identified patient group has been established.
Methodology
A retrospective medical record analysis was performed at the Center for Musculoskeletal Surgery of the Charité - Universitaetsmedizin Berlin, where patients aged 60 years or older with PHF who underwent operative treatmentfrom March 2017 to June 2018, with either PHILOS or arthroplasty and with a follow-up period of at least six months, were included. In addition, the methodological aspects of clinically translating pre-clinical knowledge of an immunomodulatory agent, Iloprost, into a sound clinical trial to obtain the necessary approvals from regulatory authorities, were described.
Results
A total of 88 PHFs in 87 subjects with a mean age of 72.9 years were recorded. The study revealed that the overall complication rate in 4-part PHF treated with PHILOS recorded the highest values, 68.8%, compared to 19% in arthroplasty cases. Further analysis showed that the nature of complications after PHILOS was less severe than the ones after arthroplasty, and revisions were performed in 8 out of 19 cases (42%) in the PHILOS group compared to 5 of 5 (100%) in arthroplasty. These observations indicated a high medical need for enhancing bone healing in osteosynthesis patients.
To conduct a clinical trial with Iloprost, a detailed estimation of proper dose and dose regimen, identifying inclusion-exclusion criteria, selecting representative endpoints, and establishing a
11 benefit-risk assessment were performed. Regulatory approval was successfully obtained from relevant authorities.
Conclusion
Elderly patients with 4-part PHF treated with PHILOS yielded the highest complication rate and could benefit from the local administration of Iloprost.
12
Chapter 1 : Introduction
1.1 Proximal Humerus Fractures (PHF)
Traumatic fractures are among the most common injuries worldwide (1). In the USA, up to 25%
of the population may suffer from musculoskeletal injury per year (2). In Germany, about 1.6 million fractures have been reported annually (3). The fracture number is expected to increase because of the extended life expectancy and consecutive age-related disorders affecting the musculoskeletal system, such as osteoarthritis and osteoporosis (4).
One of the most common traumatic fractures in the elderly population (>65 years old) is the fracture of the proximal humerus (PHF), which is ranked third after hip fracture and distal radial fracture, respectively (5, 6). The most common mechanism of trauma in this age group is mainly a simple fall from patients' height onto an outstretched hand (6, 7) (Figure 1). In Finland, a retrospective study on the patient (>18 years old) who suffered from PHF between the years 2006 and 2010 showed an overall incidence of 114 and 47 fractures per 100,000 person-years in females and males, respectively (8). This incidence increased with age and has been linked to osteoporosis, which is more common in females representing 75% of cases (7). This has been confirmed in a study conducted between 1992 to 1996 in Edinburgh, Scotland, where the incidence of PHF was 260 per 100000 persons/year in females aged 80 - 89 years and 109 per 100000 persons/year in males of the same age group (8).
Figure 1: Mechanism for low energy proximal humerus fracture in elderly individuals (9) Springer nature license number: 4737000355879
13 PHF is considered a growing challenge for health systems due to the continuous increase of cases every year. For instance, the incidence of PHF is expected to triple within the next three decades, due to the cumulative aging of the world population (10, 11). By 2050, it is expected that half of the German population will be over 50 years old (12). In Germany, the 2019 population profile shows that 18.1 million people were above 65 years old, representing 22%. According to predictions of the Federal Statistical Office, the number of people above 65 years old is expected to reach 38% by the year 2040 (13). The one-year mortality rate for PHF patients is 9.8%, while the five-year mortality rate is 28.2% (14).
Figure 2: 14th coordinated population projection for Germany. (Statistisches Bundesamt; www.destatis.de) (13)
1.2 Classification of PHF
PHF is mainly classified according to the Neer classification (15), which is the most frequently used classification in addition to the AO classification. The Neer classification of PHF refers to the four main anatomical parts of the proximal humerus: humeral head, humeral shaft, greater tuberosity and lesser tuberosity. A fracture is considered displaced if there is a fragmental displacement of more than 1 cm or angulation of more than 45 degrees (15) (Figure 3). The fracture classification, according to the number of the displaced fragments, highlights the severity and complexity of the fracture pattern with the advancement of the classification grade (16). Although
14 the outcome of PHF could be affected by many variables such as patient age, bone quality, comorbidity, and fracture reduction, the link between the number of displaced fragments according to Neer classification has been shown to be negatively correlated with the functional outcome (17, 18). Moreover, fracture severity, according to the Neer classification, has been previously used as a predictive value for the occurrence of complications (19).
Figure 3: Neer Classification of proximal humerus fractures (15)
1.3 Current clinical management strategies
Although the management of proximal humerus fractures has been studied intensively over the years, it remains one of the unsolved orthopedic problems mainly due to the absence of clear evidence-based guidelines for treatment (20). This is reflected in the lack of a consensus on the optimal treatment strategy among the scientific community (17). Currently, surgeons rely on a combination of factors when deciding on the most suitable management strategy, such as
15 classification of the fracture, degree of fracture comminution, patient bone quality (osteoporosis), patient age, physical capacity, and functional demand of the patient (21).
1.3.1 Surgery as the first-line of treatment
The current treatment strategy for PHF does not involve pharmacologic treatments since no drugs exist that are able to stimulate bone healing in fractured patients sufficiently, especially compromised elderly patients. Surgery remains the first-line treatment in displaced 3-part and 4- part PHF (22–24). Many surgical options for the treatment of PHF have been described in the literature, which can be categorized into fixation and arthroplasty. Fixation comprises the stabilization of the fragments of fractured bones by implants, such as closed reduction and percutaneous K wire fixation, open reduction and fixation with tension bands, bone sutures, cerclage wires, minimally invasive screw fixation, T-plates, intramedullary nails, and locking plate fixation. Arthroplasty comprises partial (hemiarthroplasty) or total (reverse or anatomical shoulder arthroplasty) replacement of a joint (25–28).
PHF is common in elderly females, above all, because osteoporosis is the pathological basis of the fractures (29). As a result of osteoporosis, the cancellous bone trabeculae decrease in both number and thickness, which in turn leads to poor bone quality and a decrease in bone mass (30). The osteoporotic proximal humeral bone could be described as an eggshell with the lowest bone density being in the central part of the humeral head, which is nearly devoid of bone. Therefore, the management of PHF should include the evaluation of the bone mineral density and treatment of the possibly existing osteoporosis (31). This would also reduce the incidence of potential hip fractures, which increase by 500% in the first year following PHF (32). Bad bone quality leads to poor screw purchase and endangers the fixation stability in the gold standard of fixation, angle stable plate osteosynthesis (33).
Proximal humeral locking plates
Proximal humeral locking plates, such as the (PHILOS) plate (Synthes, Switzerland), are commonly used for the fixation of PHF (34). PHILOS allows for the positioning of multiple head screws in predefined directions, which in turn enable a good purchase of screws in the bone.
Moreover, the screw heads are locked in the plate producing a one unit device, giving the maximum possible hold of the fracture fragments after fixation (35). Osteosynthesis with the PHILOS is the most common fixation method for 2-part and 3-part and, in some cases, for 4-part fractures when it is still possible to reconstruct the humeral head (36). Although frequent complications after PHILOS plate osteosynthesis reached 49%, in some studies as discussed in the
16 following section (17), PHILOS has the advantage of preserving the natural anatomy of the bone and satisfactory functional outcome (18, 37).
Figure 4: PHILOS plate (DePuy Synthes® Switzerland) (38)
Arthroplasty
Hemiarthroplasty is the replacement of the damaged humeral head with a metal joint prosthesis.
The procedure has shown to be a good treatment option for complex 3-part and 4-part fractures (31). A randomized controlled study comparing the outcome of both hemiarthroplasty and conservative management in 4-part PHF showed that the range of motion was similar in both groups. However, the hemiarthroplasty group showed less postoperative joint pain compared with nonoperative conservative management (39). Nevertheless, hemiarthroplasty is considered inferior or at least similar in terms of the range of motion when compared to conservative non- operative treatment of 4-part PHF in the elderly for the long-term (39).
1 2
Figure 5: Hemiarthroplasty 1. GLOBAL® FX™ (DePuy Synthes® Switzerland) (40) 2. Zimmer Anatomical Shoulder™ Fracture System (41)
Reverse shoulder arthroplasty (RSA) uses prosthesis components to replace the glenoid fossa as well as the humeral head, reversing the bearing partners of the shoulder joint (Figure 6). The design of the RSA enhances mechanical stability and moves the center of rotation medially and inferiorly,
17 thereby improving the function of the deltoid muscle through increasing its lever arm, which in turn compensates for the potential loss of rotator cuff function following the fracture (42).
Although RSA has been shown to be an effective procedure in cases of complicated shoulder fractures (43), it is technically demanding, and patients are left with limited options in the case of implant failure (31).
1 2
Figure 6: reversed shoulder arthroplasty
1. (DELTA XTEND™) Reverse Shoulder System (DePuy Synthes® Switzerland) (44) 2. Zimmer® Reverse System (45)
1.3.2 PHF evaluation and patient considerations
PHF typically occurs in elderly female patients after simple falls (46). These falls have a high risk of fracture incidence, which is reflected by the fact that the elderly with an active lifestyle suffer more frequently from PHF (6, 47, 48). The treatment of choice for PHF management requires a proper assessment with careful evaluation considering not only the fracture pattern and classification but also, and of high importance, the patients´ expectations. The patient evaluation process should begin with the patient history with particular attention on the independency level of the patient, the presence of previous injuries, especially rotator cuff tears and previous neurological injuries, and the patient's functional demands (49) and tolerability of the planned rehabilitation program (31). Then, the patient should be examined thoroughly, among others, for their general condition, presence of chronic diseases that could affect wound healing, immune system status, and usage of particular medication such as steroids (50). Furthermore, careful local examination of the affected arm, such as finding out if it is the dominant side, timing and mechanism of fracture, presence of other injuries, vascular status, and neurological examination (49, 51).
18 A detailed osteoporosis assessment is considered a fundamental step in the patient evaluation process as osteoporosis is not only connected to the actual PHF but also could affect the incidence of possible following osteoporotic fractures (52, 53). Proper X-ray for the shoulder joint should be obtained in anteroposterior, lateral, and axillary views, in case of complex fracture patterns, also Computerized Tomography (CT) imaging, for better-visualization and planning.
Moreover, Magnetic Resonance Imaging (MRI) could help in assessing the rotator cuff status, since tears accompany the PHF in up to 40% of patients (54). Rotator cuff tears at time of injury were found to be significantly linked to patients' functional loss at one year follow-up (55).
1.3.3 Individualization of the treatment
The treatment choice process for PHF in the elderly is not a simple choice and varies significantly from one patient to another, particularly for 4-part PHF (31). This variation could be explained by the absence of strict treatment guidelines for PHF treatment. Previously, the choice of treatment was mainly determined depending on fracture radiology and on fracture classification. However, this concept has been revised as depending only on these two factors was found to be unreliable and unreproducible (56–58).
The controversies in treating PHF in the elderly started early in deciding whether surgical or non- surgical treatment is a better choice for the patient. Some PHF patients have an obviously clear indication for surgery such as in open fracture, pathological fracture, vascular injury, or neurological injury which could require surgical fixation to secure the repair (36), while other patients have a relatively clear indication for nonsurgical treatment, such as in non-displaced fractures or patients with cerebral stroke or other permanent neurological impairment at the same fracture side. These patients would not gain benefit from surgical management. Moreover, conservative treatment may be preferred for unstable patients and who could only be treated surgically if the patient’s general condition improved (50). However, also in patients treated with arthroplasty, the surgeon should consider that early surgery (within the first four weeks) is an essential variable for the functional outcome (59, 60).
The surgical treatment options for 4-part PHF encompass mainly angle stable plate osteosynthesis and arthroplasty. Murray et al. (36) describe criteria that could help in the proper selection of the surgical treatment for the 4-part PHF. The criteria categorize the indication into either PHILOS plate or primary arthroplasty with cases where bothtreatment modalities are indicated (figure 7).
It has been reported that PHF patients above 50 years old with a head split injury should be treated with arthroplasty; this was explained by the significant damage of the articular surface that could affect the fragments vascularity, which in turn increases the incidence of avascular necrosis (61).
19
1.4 Treatment outcomes and complication rates
The outcome of fracture treatment depends on several factors that can be categorized into i) patient factors: age, presence of chronic diseases, bone quality, and degree of fractures, or ii) treatment- related factors: choice of either conservative or operative treatment, the operative technique used and skills of the surgical team.
The complication rate of managing PHF varies markedly between different studies for a given specific method of treatment. For example, the overall complication rate for locking plate fixation was reported to be between 9.7% and 57% (Table 1). Similarly, the complication rate of RSA was reported to fall between 4.8% and 68% and reached in some studies up to 75% (62, 63). The reason for this difference in complication rates between studies could be attributed to the heterogeneity of the studies concerning several factors, such as the age of the study population, fracture classification, the method of outcome evaluation, and the difference in studies follow-up duration (64). Compared to RSA, hemiarthroplasty previously showed a higher revision rate and inferior results concerning pain relief, patient satisfaction, and range of motion (65–68). A decrease range of motion in hemiarthroplasty mainly occurs in the long run (mean 3.7 years) (69), which is due to possible mal-union of the humeral tuberosities (29, 70, 71). This, in turn, leads to a defective range of motion, especially in raising the hand above the head (31).
PHILOS
Good bone quality
Physiologically young
Active patient with high functional demand
Reducible fracture pattern
Gray zone: factors affecting the proper surgical decision
previous activity
functional demand
Comorbidities, including osteoporosis
Tolerability of revision surgery
Initial fracture displacement
Surgeon experience
Arthroplasty
Severe shoulder osteoarthritis
Highly comminuted fracture
Decreased functional demands
Treatment of fixation complication
Head –split fracture (61)
Figure 7: Criteria of treatment choice for the 4-part PHF
20 Table 1: Reported complication rates for locking plate fixation in proximal humerus fracture
Study Complication rate Number of patients Median follow-up Ref.
Aksu et al. 9.7% 103 19 months (72)
Koukakis et al. 15% 20 16.2 months (73)
Agudelo et al. 19% 153 55 months (74)
Haasters et al. 21.4% 646 12 months (75)
Egol et al. 23.5% 51 16 months (76)
Hepp et al. 31.3% 83 12 months (77)
Owsley et al. 36% 53 44 months (78)
Klug et al. 37.8% 66 12 months (64)
Jost et al. 57% 121 22 months (79)
The complication rate of managing PHF does not only vary between methods of treatment, as stated above, but also between different clinical centers. For instance, tertiary hospitals are known to receive and manage more complex referral cases that could explain higher complication rates.
For these reasons above, it is challenging to infer accurate rates of complication of managing PHF from the literature. A more effective approach would be to rely on the data derived from each center.
1.5 Complication patterns and associated risk factors
1.5.1 Complication patterns
There are different surgical procedures for PHF,particularly for complex injuries in the elderly, with different complications for each procedure. Nevertheless, the common possible complications after surgical treatment of PHF can be summarized as follows:
a) Loss of reduction: Loss of reduction can be considered a severe complication and one of the most frequent causes of revision surgeries (18). It can be diagnosed with either fracture angulation of ≥ 10 degrees in any direction or loss of the humeral head height ≥ 5mm (80).
It is a common complication, particularly in elderly patients, which is linked to osteoporosis. The prevention of loss of reduction is difficult, and loss of reduction frequently ends with low functional outcomes (81).
b) Infection: Infection after proximal humerus fracture treated with open reduction and internal fixation (ORIF) is a feared complication. However, the soft tissue coverage and good blood supply of the surgical site prevent against infection, and therefore infections are relatively infrequent after osteosynthesis with 2.9% of all procedures (75, 82, 83). The
21 reversed shoulder arthroplasty showed an infection rate of about 0.76% at 90 days follow- up, which increased to 2.4% after the first year, and to 6.74% at 2-year postoperative follow-up (62). Infections can be divided into acute or delayed infections (84). Delayed infections can either occur as low-grade infections up to three years after ORIF or arthroplasty, and are caused by intraoperative contaminations of the implants, or as haematogeneous infections after many uneventful years, especially after arthroplasty. The latter are mostly caused by transient bacteremia. The infection management is always a complicated and costly process which always includes surgical intervention with the procedures depending on the type of infection. The required surgical procedures include debridement, together with either implant retention in acute infections, or removal of all implants in chronic infections (85, 86).
c) Screw cut-out and long screw: penetration of the screw tip out of the medial cortex of the humeral head is a potential complication following surgery (87). This complication is common in elderly patients and linked to low bone quality and osteoporosis and occurs mainly in unstable fractures (78). Screws cut-out is associated with delayed healing and/or bone necrosis as a sequence of loss of reduction with protrusion of the upper screws into the joint. The screw penetration into the joint space could also occur at the time of surgery as a technical error (88).
d) Pseudo-arthrosis: A relatively uncommon complication of PHF, is pseudo-arthrosis after ORIF. Pseudo-arthrosis is a form of nonunion, where fibrous tissue is formed between tissue fragments. Pseudo-arthrosis occurs more frequently with Neer type Ⅱ surgical humeral neckfractures, which could be explained by excessive mobility in the fracture site (89). The pseudo-arthrosis treatment can be difficult due to local factors such as connectivity of the fracture to the synovium and the stress forces produced by muscles and ligaments around the fracture. Moreover, osteoporosis and cavitation of the humeral head pose challenges, which increase with aging. The surgical treatment of the pseudo-arthrosis is challenging and can lead to an unfavorable functional outcome even when treated with arthroplasty (89, 90).
e) Nonunion: Nonunion is defined as the failure of bone trabeculation to cross the fracture gap. The clinical presentation usually includes persistent pain and loss of function of the shoulder. Nonunion frequently requires revision surgery (91). Therefore fracture nonunion has been defined by Calori et al. (92); this is the fracture that will not unite without further intervention.
22 f) Avascular necrosis: Avascular necrosis (AVN) of the humeral head can be defined in traumatic cases as bone death following deprivation of blood supply. The dead bone under stress forces is prone to flattening and collapse, leading to an abnormal shape of the humeral head and joint incongruity and is often associated with pseudo-arthrosis (31).
g) Pseudo-paralysis: Pseudo-paralysis can be considered as one of the unsolved challenging complications of shoulder surgery (93). The definition of pseudo-paralysis varies in the literature, but it is mainly defined as the loss of active shoulder elevation more than 90 degrees with free passive motion. Pseudo-paralysis is linked to rotator cuff tear and leads to low functional outcomes affecting the quality of life (93).
h) Instability and Dislocation: Instability refers to the inability to keep the humeral head in the glenoid fossa (94). Instability is one of the most common and challenging complications that can follow arthroplasty and one of the leading causes of revision surgery (95, 96). The management of joint instability needs careful evaluation of the cause and managing the predisposing factors such as humeral shortening, excessive medialization, together with the proper choice of the implant and soft tissue management (96). Shoulder dislocation after arthroplasty can occur either early in the first three months or delayed (after 3 months). Early dislocation can be managed conservatively with closed reduction under anesthesia, providing there is no relevant biomechanical problem causing the dislocation (97). Delayed dislocation usually requires revision surgery after careful evaluation of the cause of instability (96).
1.5.2 Associated risk factors
The overall healing capacity is known to be decreased in the elderly; this decrease could affect bone healing and lead to delayed healing or even nonhealing with its subsequent complications, as stated above (98). Aging is linked to many physiological changes that could affect bone healing.
Many studies have evaluated the differences in the bone healing process between young and elderly and revealed several causes of delayed bone healing in the elderly (99–101). PHF is common in old age females and strongly linked to low bone mineral density as one of the fragility fractures. Its correlation with fragility is even more pronounced than the linkage with fractures of the hip, distal radius, or spine (29). Therefore, the management of PHF should include not only the evaluation of bone mineral density and treatment of the possible existing osteoporosis but also a thorough analysis of fragility and possibilities of prevention strategies (31, 102).
The relationship between the immune system in the elderly and the bone healing process has been previously established (100, 101, 103). This link has been established concerning physiological
23 bone turnover as well as pathologically as in fragility fractures (104). The initial inflammatory phase of bone healing has a significant role in initiating bone healing cascade (105). Typically in the bone healing cascade, the initial pro-inflammatory phase is followed by the anti-inflammatory phase; this switch is critical for proper bone healing (99). The initial inflammatory phase of bone healing is a necessary step to initiate the healing cascade via sending a chemotactic signal, which helps to invite more cells, especially endothelial cells, to the fracture hematoma (106). This phase has been shown to reach its peak within the first 24 hours following bone fracture (107), then declines, and the inflammatory cytokines start to decrease with a predominance of the anti- inflammatory cytokines. The upregulation of the anti-inflammatory factor expression is associated with an increase of expression of angiogenic factors such as heme oxygenase (HMOX), Vascular endothelial growth factor (VEGF), and Glucose transporter 1 (GLUT1), which are beneficial for bone healing (107, 108). It has been previously reported that a prolonged pro-inflammatory phase could impair angiogenesis and disturb the osteogenic processes leading to a delay in the healing progression of long bone fractures or could even lead to non-unions (101, 107, 109, 110).
Moreover, the initial inflammatory phase of bone healing is typically characterized by a large population of macrophages of the M1 phenotype, which has the ability to release cytokines that trigger and promote the inflammatory response (111, 112). Later in the anti-inflammatory phase of bone healing, the macrophages are mainly of the M2 phenotype, which releases growth factors and anti-inflammatory cytokines (111, 113). The switch between M1 into M2 at the proper time is of great value in regulating the inflammatory phase and affects the bone healing process (99).
However, with aging, the ability to control the pro-inflammatory phase is decreased, leading to a prolonged and high amplitude pro-inflammatory phase, which in turn negatively affects bone healing (99, 114–116).
Additionally, immunologically restricted patients such as those with autoimmune diseases or malignancies often suffer from delayed or insufficient fracture healing, which has been found to be due to the vigorous inflammatory activity on cellular and humoral levels at fracture sites (117).
The analysis of the fracture hematomas and/or the surrounding bone marrow of these patients showed a significant difference in the initial inflammatory phase compared to the healthy control group. The immunologically restricted patients show a higher population of immune cells with high levels of pro-inflammatory cytokines, which could be one of the reasons that explain healing problems in such patients (117).
Differences between young and old cell populations strengthen this assumption; as with aging and the continuous exposure to pathogens, the memory T cell population such as Terminally Differentiated Effector Memory CD8+T (TEMRA) increases, leading to a high CD8/ CD4 ratio.
24 CD8+T (TEMRA) cells have been proven to play a crucial role in controlling bone cells through specific cytokines that control the osteoclasts via specific receptor activator of nuclear factor κB (RANK) on the cell surface (118). These cells release RANK-ligand (RANKL) that is capable of stimulating osteoclasts and hence increasing bone resorption, which, as a result, delays the healing process (119). The link between CD8+T (TEMRA) cells and the delayed union has also been further proven through the finding of a high population of CD8+T (TEMRA) cells in the delayed bone healing fracture site (109, 120). Similarly, fractures in an animal model with a low population of CD8+ show enhancement of the bone healing process (101).
Moreover, CD8+T (TEMRA) cells were found to be enriched in fracture hematomas; these cells were the major producers of Interferon gamma /Tumor necrosis factor-alpha (IFN ɣ/ TNFα), which inhibit osteogenic differentiation and the survival of human mesenchymal stromal cells (101). On the other hand, the T regulatory (Treg) subtype revealed a positive impact on both wound and bone healing (121–125). Additionally, bone healing capacity was found to be improved in the (Treg) high population animal model (121–125). Therefore, balancing the CD4+ Tregs / CD8+ effector memory cell ratio could enhance the local fracture milieu and control the inflammatory phase in a way that could benefit the bone healing process in elderly patients (107, 126).
1.6 Novel concepts in bone regeneration
PHF in elderly patients has shown increased rates of healing delays with the consequence of fracture complications. As given in detail above, the complication rate due to deficient bone quality in elderly patients has reached up to 57% for surgically treated patients (79). Therefore, these patients exhibit a high medical need for a biological solution. Immunomodulatory therapy has emerged as a potential therapeutic strategy that can benefit fracture patients with unfavorable immune responses. Such therapies are expected to reduce the risk of delayed bone healing in fracture patients with a potential dysregulation of the immune reaction and altered immune cell compositions in the fracture site through downregulating CD8+ cytotoxic cells, which has a potentially unfavorable effect on bone healing. Moreover, immunomodulatory therapy reduces the TNF-α and IFN- γ secretion of T cells and further supports macrophage polarization towards an anti-inflammatory type. In other words, immunomodulatory therapy aims to downregulate the inflammatory phase, which is known to be of high amplitude and long duration in this specific age group due to an over-reactive immune response (101, 120, 127).
In recent years, the potential role of Iloprost as an immunomodulatory agent was found to be promoting an anti-inflammatory and immunosuppressive effect (128, 129). Iloprost is a synthetic analogue of prostacyclin PGI2, a product of the cyclooxygenase pathway metabolizing arachidonic
25 acid constitutively in human cells, which dilates systemic and pulmonary arterial vascular beds.
The U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA) approved Iloprost in 2004 and 2003, respectively, for the treatment of Primary Pulmonary Hypertension (PPH). Moreover, Iloprost has been used in cases of Buerger disease (thromboangitis obliterans), scleroderma, and ischemia (130), in addition to severe pain caused by sickle cell crisis, Reynaud phenomenon and systemic lupus erythematosus. Iloprost acts by causing vasodilatation in the microcirculation, reducing the capillary permeability, preventing the adhesion of thrombocytes, improving the viscosity of distal vessels, and reducing the generation of oxygen free radicals and leukotrienes (131, 132). Furthermore, the drug has been previously used as an off-label treatment for bone marrow edema in initial cases of osteonecrosis and showed promising therapeutic results (132–135).
The immune-modulatory effect of Iloprost has been investigated in the context of bone regeneration (100). In vitro studies confirmed the immune-modulatory properties of Iloprost and the postulated positive osteogenic effect (100). In a proof of concept in vivo study, the local Iloprost application in a mouse osteotomy during the early bone healing phase showed a positive impact on bone healing, where Iloprost within a fibrin-based release system was inserted during surgery into an osteotomy gap of a mouse to delay the release of Iloprost to the surgical site (100).
This delay allowed the initial pro-inflammatory phase to continue and initiate the healing cascade of the local fracture milieu (107, 126). Another preclinical experiment in a sheep model was performed, where Iloprost was applied in a hydrogel scaffold during surgery in the bone drilled hole (136). No adverse effects nor local toxicities were observed with the local application of Iloprost in this large animal model, which could be evidence for the local safety of Iloprost application.
1.6.1 The potential benefits of Iloprost in bone healing
According to the performed and published preclinical findings to date, the benefits of Iloprost as an immune-modulatory agent in inducing bone regeneration can be summarized as follows:
1.6.1.1 Immunomodulatory Effects of Iloprost on cytokines:
Iloprost reduced the concentration of secreted IFNγ and TNFα of T cells creating a favorable milieu for MSC differentiation. This effect has been tested in vitro on murine MSCs in two different Iloprost doses (300 nM and 3 μM) (100). Both cytokines (IFNγ and TNFα) have a significant role as signaling molecules in bone repair, particularly in the early fracture healing phase with overly high amounts of them negatively affecting bone repair by diminishing the formation of the mineralized matrix by MSCs (101).
26 1.6.1.2 Immunomodulatory Effects of Iloprost on CD8+ T cells:
The preclinical data showed that the presence of 3 μM Iloprost affects the isolated CD8+ T cells leading to a decreased secretion of IFNγ and TNFα (100). CD8+ T cells are one of the primary producers of pro-inflammatory cytokines in the early bone repair phase (101).
1.6.1.3 Immunomodulatory Effects of Iloprost on macrophages:
Iloprost led to the downregulation of pro-inflammatory and the upregulation of anti-inflammatory cytokines by MΦ, M1, or M2 polarized macrophages. Macrophages are responsible for the clearing of the cell debris through early infiltrating the fracture area and are necessary for the recruitment of further cells adverse for the progression of the healing cascade due to their secreted cytokine profile (4).
1.6.1.4 Iloprost showed no negative impact on the osteogenic and chondrogenic differentiation capacity of MSCs:
MSCs are the precursor cells for both cartilage-producing chondrocytes and bone-forming osteoblasts. Iloprost showed no negative effect on the osteogenic capacity of MSCs when added to monolayers of MSCs that have been cultured for 14 days in osteoinductive media (100).
Additionally, Iloprost did not hinder the chondrogenic differentiation of MSCs (100).
1.6.1.5 Iloprost promotes fracture healing in vivo:
Iloprost embedded in a fibrin clot (used as a delayed-release system) was inserted during surgery in an osteotomy gap of a mouse osteotomy model system. This delayed release allows the initial pro-inflammatory phase to proceed and to initiate the healing cascade. Micro-computed tomography (μCT) analysis 21 days post-surgery showed an improved healing outcome of the mice receiving Iloprost in comparison to the control group (an increase of both bone volume and total callus volume as well as the ratio of bone volume/total callus volume) (100). Additionally, histomorphometric (IHC) analysis of the tissue distribution around the gap after 21 days in the Iloprost treated group showed a significantly higher amount of mineralized bone and cartilage tissue (100). Finally, IHC analysis of about three days post-osteotomy showed the starting shift of the pro-inflammatory into the anti-inflammatory phase in the mouse osteotomy model system (100).
1.6.1.6 Iloprost effect on bone microcirculation:
Iloprost has also been previously used as an off-label treatment for bone marrow edema in early cases of osteonecrosis and showed promising therapeutic results (132–135, 137). Iloprost has been successfully used as an IV infusion to treat AVN safely with minor and totally reversible side
27 effects (138). Iloprost vasodilator effect is found to enhance microcirculation and increase local blood flow (138) by causing vasodilatation in the microcirculation, reducing the capillary permeability, preventing the adhesion of thrombocytes, improving the viscosity of distal vessels, and reducing the generation of oxygen free radicals and leukotrienes (131, 132).
1.7 Clinical trial approval
The process of clinical trial approval falls under the Directive 2001/20/EC (139) of the European Parliament and Council, which regulates the performance of clinical trials in humans while protecting their rights and dignity according to the Declaration of Helsinki (140, 141) and the good clinical practice guidelines (142). In order to obtain approval for a clinical trial in humans, the applicant should demonstrate a profound benefit-risk assessment and guarantee participant rights, well-being, and data protection throughout the entire clinical trial. Two simultaneous application processes need to be initiated and approved before starting a clinical trial, one at the ethics committee and the other at the relevant competent authority, which in this case was the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte BfArM) because the immunomodulatory agent Iloprost is a small molecule drug.
1.7.1 Ethics committee
The state office for health and social affairs (Landesamt für Gesundheit und Soziales (LAGeSo)) sets up the ethics committee of the state of Berlin to evaluate clinical trial applications, according to the German regulation for approval, and implements the clinical trial with medicinal products in humans (GCP-V) (143) and section 42 of the Medicinal Products Act (Arzneimittelgesetz – AMG) (144). Within ten days of receiving the application, the ethics committee is responsible for informing the sponsor that either a correct application has been received, or for asking the sponsor to resubmit any missing documents within fourteen days. The review timeline is one month between the formally completed submission and the first oral consultation for a Phase 1 mono center clinical trial. During the evaluation process of the application, the ethics committee can only request additional information from the sponsor once. The deadline for the ethics committee response is postponed until the additional information is received. Then, the ethics committee sends their reasoned assessment to the sponsor and the competent higher federal authority.
The following is the list of documents that are required to be submitted to the ethics committee in both paper and electronic forms:
1. Cover letter, which should include study data such as the name of the study, EudraCT number, sponsor name, study center, the list of all documents, their version and date, in addition to the confirmation that the electronic and paper versions are identical.
28 2. Application checklist form (list of all required documents) according to the 12th
amendment to the AMG and the GCP-V (143, 145).
3. EudraCT: (European Union Drug Regulating Authorities Clinical Trials database). This is a registry of the interventional clinical trials operated by the European Medicines Agency and used by the member state competent authority to approve and monitor the clinical trial.
4. Module 2 (general overview of the trial)
5. EudraCT confirmation letter sent to the applicant after initiation of the new EudraCT 6. Sponsor responsibility (principal investigator authorization letter)
7. Study protocol German summary that should include the general outlines of the study protocol
8. Study protocol: this is one of the most crucial documents in the clinical trial application.
It should include: a) general data as the name of the study, sponsor, monitor, principle investigator, and the clinical lab or other technical departments. b) background information of the investigational product. c) study objectives d) study design e) participants selection criteria f) assessment of efficacy and safety as well as study statistics g) data access, handling, record keeping, quality control measurements, ethics considerations, financial overview, and publication policy (GCP) (142)
9. Risk-benefit assessment
10. Investigational Brochure (IB) and the professional drug information: the IB should include all relevant clinical and nonclinical data on the investigational drug and the rationale for conducting the clinical trial. In the case of using previously marketed drugs, the summary of product characteristics should be attached. In the case of using an already marketed drug in a new indication, the IB should be prepared to be specific for the new use. (GCP) (142) 11. Patient information sheet and the informed consent form. Both documents should be
written in easily understandable language for the patients with detailed information about the trial, mentioning the possible risks and benefits of the investigational drug in addition to including all data rights and responsibilities of the participants, and providing data on study insurance.
12. The study insurance documents. According to the (AMG), the insurance for the clinical trial should be at least 500000 Euro per study participant, which can be paid in cases of permanent disability or death in connection with clinical trials (144)
13. Principle investigator and sub-investigator (deputy) qualification documents and confirmations (CV, training like the GCP, financial interest, privacy and data protection agreement)
29 14. Study financial cost estimate: an overall study financial overview
1.7.2 Federal Institute for Drugs and Medical Devices (BfArM)
According to the GCP-V (143) and the section 40- 42 of the (AMG)(144), the relevant competent authority in this trial is the Federal Institute for Drugs and Medical Devices (BfArM) because the investigational drug (Iloprost as an immunomodulatory agent) is a small molecule drug. After receiving the application, the BfArM will respond to the sponsor within ten days either that their application is complete, or inform the sponsor of any missing document. The sponsor then has fourteen days to resend the missing document to the BfArM. Starting from the date of formally complete clinical trial submission, the BfArM has 30 days to evaluate the application and either approve or object to the conduct of the clinical trial. In the event of objecting to the trial, the sponsor has 90 days to reply to the BfArM objections by submitting additional documents/information. Finally, the BfArM has fifteen days to give the final decision of the whole application process. The ethics committee will also receive a copy of this final BfArM decision.
The following list of documents should be prepared in accordance with the European Commission 2010/C82/01 (146) and submitted to the BfArM in both paper and electronic forms:
1. Cover Letter
2. EudraCT and confirmation letter for the EudraCT number 3. Study protocol
4. Investigator’s Brochure (IB)
5. Investigator Medicinal Product Dossier (IMPD). This is a critical document in the clinical trial application; the IMP is defined in the Directive 2001/20/EC (139) Article 2 (d) as “a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with marketing authorization but used or assembled (formulated or packaged) in a way different from the authorized form, or when used for an unauthorized indication, or also when used to gain further information about the authorized form (139)”. This means that even the reference products such as placebo should be considered as an IMP. The given data should include all data regarding the general information and structure of the drug, detailed manufacturing data including materials and steps control, characterization, impurities, control of the drug substance, reference standards, container closure system, and data on the drug stability (147). In the case of using a previously authorized drug, in the clinical trial, it is sufficient to mention the marketing authorization number and marketing authorization holder, and it is possible
30 to refer to the data of preclinical and clinical use of the drug as well as data regarding the toxicology and safety profile of the drug (147).
6. Risk and benefit assessment
This section includes a detailed analysis of the data, either clinical or nonclinical, to elaborate on the benefits and risks of using the investigational product. Risk and benefit assessment should mention any previously terminated clinical trial for safety issues discussing the cause of termination. The safety margin should also be mentioned by discussing the clinical relevance of any previously available clinical or non-clinical data (146). Moreover, it is essential to prove that the expected benefits outweigh the possible potential risks during the whole trial period during the trial (139).
7. Non Investigational Medicinal products dossier (Non-IMPD) if applicable. The non-IMPD is a medicinal product, for example, that is used in the trial as a concomitant (148).
8. Good manufacturing practice (GMP) (Manufacturing authorization as a proof for GMP compliance, this is only applicable if the previously authorized drug will not be used in its original form)
9. Labeling (if applicable)
10. Administrative Documents (sex distribution, further treatment, data protection declaration, costs declarations)
11. Scientific Advice (if applicable)
12. Genetically Modified Organisms (GMO) (if applicable) 1.8 Aims of the study
Regardless of the availability of different treatment options for PHF, the choice of the optimal management approach remains debatable, especially for patients above 60 years of age with 3-part and 4-part fractures, (149). Notably, members of this age group more frequently have a more experienced adaptive immune system than a younger collective, and the accompanied unfavorable immune response can lead to delayed bone healing, as discussed above (100, 107, 126). Moreover, the analysis of all surgical procedures outcomes and complication rates significantly differ between different treatment centers. Analyzing the outcome results and complication rate of current surgical management strategies for elderly patients with PHF in a leading academic center, where a high competence in fracture management with osteosynthesis and arthroplasty is present, could serve as a reference for the evaluation of the respective surgical techniques. The correlation of patients with a certain fracture pattern with the outcome can assist in considering their enrolment in an intervention study for the planned immunomodulatory therapy.
31 As such, the aim of this thesis was divided into two stages. The first aim focused on measuring the outcome of surgical management strategies, including complication and revision rates, of the two most commonly performed surgical procedures (angel stable plate osteosynthesis and arthroplasty) in elderly patients with PHF via a retrospective database analysis performed at the Center for Musculoskeletal Surgery at the Charité - Universitätsmedizin Berlin. This enabled us to identify the group of patients who could gain benefit from novel therapeutic approaches improving bone healing. The second part of this study focused on translating a scientifically sound novel immunomodulatory approach from the pre-clinical stage to phase I, Ⅱa clinical trial that could improve the healing outcomes for the identified group of patients.
Specific aims:
1. To perform a literature review and identify gaps in knowledge regarding the current management strategies of PHF, the magnitude of complications following PHF management in elderly patients, and the potential benefits of immunomodulatory therapies.
2. To assess which surgical procedure for PHF is associated with lower complication and revision rates based on fracture classification.
3. To propose a novel therapeutic approach (immunomodulatory therapy) by translating preclinical data into a clinical trial that may help in improving the outcome of elderly patients with PHF.
32
Chapter 2 : Methods
The methodology of the study is divided into two sections. The first section focuses on a literature review and retrospective medical record analysis. This research was based on a review of data from patients suffering from PHF who had been surgically treated between March 2017 and June 2018 at the Center for Musculoskeletal Surgery (CMSC) of the Charité - Universitätsmedizin Berlin. The second part focuses on the development of a scientifically sound clinical testing strategy for an investigational immunomodulatory molecule.
2.1 Retrospective study
2.1.1 Literature review and formulating the research question
Research on PHF is known to lack comparative trials and having been performed on heterogeneous study populations, leading to the unavailability of reliable clinical recommendations (150). On the other hand, there is a rapid expansion in the literature for PHF focusing on new technologies and procedures. Due to this diversity in treatment strategies, and a substantial lack of clinical reports describing complication rates, particularly in elderly patients, performing a literature review to map and fill in the apparent knowledge gaps was seen as a necessary first step. PubMed, EMBASE, and MEDLINE databases were searched for the literature reporting on elderly patients treated surgically for (PHF). The search specifically focused on prospective clinical studies and retrospective observational studies investigating the outcome and the complication rate of surgical treatment of PHF. The search words included (proximal humer* fracture OR humer* head fracture AND age* OR elder* OR old* AND surgical OR surgery OR operat* AND treatment OR management OR outcome). The search scope was narrowed to the English language literature and from 2000 to 2020 (08.09.2020). Search filters applied were full text available, clinical trial, randomized control trial, review, and exclude duplication. The inclusion criteria were randomized control studies and cohort studies that recruited patients 60 years old or above, received operative treatment for PHF with any comparator, and follow up of at least one year. The exclusion criteria were case report studies (Figure 8).
The literature review has led to the formulation of the following study questions:
“Which group of patients in the elderly population with PHF have the least favorable clinical outcomes after surgical intervention?” and:
“Which clinical trial design investigating a local immunomodulatory therapy would have the potential of showing an effect on the outcome of PHF treatment?”
33 The research question was designed following the ‘PICOT’ model as follows:
the patient population being studied: elderly patients suffering from PHF
the intervention: treated with arthroplasty or ORIF (PHILOS)
the condition: PHF based on Neer classification
the outcome of interest: complication rates
the timing of the analysis: six months after surgery
The complications discussed in this study were of Grade 2 or higher according to the surgical complication classification described by Dindo et al. (151). According to Dindo et al., Grade 1 is any abnormal postoperative deviation, which includes events of minor risk that does not require therapy except simple medications such as analgesic, antipyretic or antiemetic. Grade 2 includes complications that may need either medical treatment (except the simple medications of Grade 1) or prolonged hospital stay by two times more than the average hospital stay of a similar procedure.
Grade 3 encompasses any complication that could require invasive intervention. In contrast, Grade 4 is any complication that could lead to organ resection or permanent disability, and Grade 5 is any complication that could lead to death (151).
2.1.2 Study center
This study was based on single-center retrospective research. The study was carried out in the Center for Musculoskeletal Surgery (CMSC) of the Charité - Universitätsmedizin Berlin, considered as one of the largest orthopedic and trauma centers in Germany. The center is located at both Charité campuses, Mitte and Virchow Klinikum, with more than 8200 hospital admission cases and about 8500 surgical procedures every year.
2.1.3 Study design
This study is a retrospective medical record review study. The center’s medical database was searched for all primary treatments of PHFs between March 2017 and June 2018 in patients aged 60 years or older utilizing the corresponding ICD-10 codes. All individual patient identifiers were removed, and patients' data were given a serial identification number (anonymized) when included in the study.
2.1.4 Patient selection
Patients aged 60 years or older with PHF who underwent operative treatment from March 2017 until June 2018 were the target group for this study. One hundred and five patients with PHF were identified. Patient selection was based on the ICD-10 coding (152) (S42.2 fracture of upper end of the humerus):
